Anti-malarial drug shuts down cell “recycling” in brain cancer

In 2016, Yoshinori Ohsumi received the Nobel Prize in Physiology or Medicine for his wonderfully orchestrated research carried out in the 1990s that led to the discovery of the cellular machinery used to recycle, break down, and destroy, old and unwanted molecular parts. This process, called autophagy, is essential for the maintenance of normal, healthy cells. And as with many of these normal cellular processes, when autophagy goes wrong it can contribute to the development and progression of cancer.

Autophagy has fascinated cancer researchers for decades because of its link to the way cells respond to stress and damage. Cancer cells are under more stress than normal because they are dividing all the time, and often have to survive in environments deprived of nutrients and oxygen. And so, they rely on autophagy to survive.

Earlier this year, Dr Kasper Rouschop, based at Maastricht University in the Netherlands, published new data revealing how targeting autophagy in cancer cells could be a way to treat difficult cancers, such as a type of brain tumour called glioblastoma. Their research has even shown that a widely used anti-malarial drug, called chloroquine, seems to improve survival in glioblastoma patients when used in combination with conventional treatments.

Dr Kasper Rouschop told us: “The prognosis for glioblastoma patients is very poor. Due to the location in the brain, many drugs cannot reach the tumour due to the existence of a ‘blood-brain barrier’. This unique system normally protects the brain from exposure to harmful products delivered via the blood, but in this case, also limits the delivery of cancer drugs.”

“Solid tumours, like glioblastomas, also have areas that are deprived of oxygen. Cells within these regions are more resistant to conventional therapies such as chemo- and radiation therapy.”

Autophagy is activated when cells becomes stressed, such as in areas deprived of oxygen commonly found in solid tumours. The process is kick-started by the cells producing something called an ‘autophagosome’. This bubble-like structure captures old bits of cellular machinery that need to be recycled. To start the recycling process the autophagosome needs to fuse with another ‘bubble’ called the lysosome, which contains enzymes that break down the cellular parts. And this is where chloroquine comes in. It builds up in the lysosome bubble and stops the enzymes from working, effectively blocking autophagy from working.

Chloroquine is able to cross the blood-brain barrier, and target cells that are surviving under stressful conditions, such as glioblastoma cells living in oxygen-deprived tumours. This combination of factors may explain why chloroquine improves survival in patients with this type of brain tumour. Dr Rouschop certainly thinks it’s something worth pursuing:

“We are currently recruiting glioblastoma patients to determine the correct dose of chloroquine that can be administered safely to patients. Once the correct dose has been identified, we will start a phase II clinical trial to assess the potential therapeutic benefit of combining conventional glioblastoma therapy with chloroquine.”

“But we are not the only ones. Several clinical trials have been initiated in glioblastoma patients that use chloroquine or similar compounds, so we expect to see data on how useful it is as a treatment very soon”.

Chloroquine could prove to be a very useful drug indeed. Research in the lab, and the small number of patients who have had chloroquine as part of clinical trials, shows a clear benefit. Chloroquine has also been used safely for decades to treat of malaria and rheumatoid arthritis. However, caution is needed when treating cancer patients as Dr Rouschop explained:

“We have to keep in mind that chloroquine will be combined with cancer therapies including chemotherapeutic drugs. It is extremely difficult to predict interactions and the dose of chloroquine that can be safely combined with other treatments. That is something we have to carefully determine first”.

The support you give makes research like this possible. Without your support, Dr Rouschop would not have been able to complete research that has enabled his team to set up a clinical trial to test chloroquine in patients with glioblastoma.

Dr Rouschop said: “You make a lot of different cancer research projects possible, this is very important and I am thankful for that. I strongly believe that the combination of all of our efforts will ultimately lead to improved cancer therapy. This will still require a lot of time and effort, but as we have seen in the last 40 years, progress has clearly been made.”

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